Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan

Abstract

Translational efficiency correlates with longevity, yet its role in lifespan determination remains unclear. Using ribosome profiling, translation efficiency is globally reduced during replicative aging in budding yeast by at least two mechanisms: Firstly, Ssd1 is induced during aging, sequestering mRNAs to P-bodies. Furthermore, Ssd1 overexpression in young cells reduced translation and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, phosphorylation of eIF2α, mediated by the stress kinase Gcn2, was elevated in old cells, contributing to the global reduction in translation without detectable induction of the downstream Gcn4 transcriptional activator. tRNA overexpression activated Gcn2 in young cells and extended lifespan in a manner dependent on Gcn4. Moreover, overexpression of Gcn4 sufficed to extend lifespan in an autophagy-dependent manner in the absence of changes in global translation, indicating that Gcn4-mediated autophagy induction is the ultimate downstream target of activated Gcn2, to extend lifespan.

Multi-faceted deregulation of gene expression and protein synthesis with age

“…The described translational downregulation of transcripts encoding components of protein synthesis machinery was not detected in the pairwise comparison of gene expression in liver and brain of young and old rats, performed by an earlier ribosome profiling study (14). However, the findings are consistent with the translatome changes during yeast replicative aging (13). Interestingly, as the yeast transcripts encoding translation-related components do not exhibit 5' TOP motifs (47) and thus are unlikely to be regulated by mTOR in the manner similar to the mammalian transcripts, in this case the reduction of both overall translation and ribosome protein synthesis is achieved by distinct mechanisms, i.e.…”

“…Increased promoter methylation in ribosomal RNA genes and decreased ribosomal RNA concentration during aging were also reported (11). In addition, down-regulation of translation with age was confirmed in vivo in the sheep (12) as well as in replicatively old yeast (13). Recently, analyses of liver and brain of 6-and 24-month old rats revealed age-related translatome changes in mammals (14).…”

“…Interestingly, as the yeast transcripts encoding translation-related components do not exhibit 5' TOP motifs (47) and thus are unlikely to be regulated by mTOR in the manner similar to the mammalian transcripts, in this case the reduction of both overall translation and ribosome protein synthesis is achieved by distinct mechanisms, i.e. activation of the GCN2/eIF2α regulatory pathway and elevated mRNA recruitment to P-bodies in aging cells (13). Interestingly, the GCN2/eIF2 axis was recently shown to regulate translation of 5' TOP mRNAs also in mammals (48), so its possible link with the observed phenomenon is worthy of further investigation.…”

Defining the RNA interactome by total RNA ‐associated protein purification

“…It was, therefore, unexpected that reduced RNA interactions were seen for eleven proteins classed under the GO term “P‐body”. Exceptions included the global translation repressor Ssd1 (Kurischko et al , ; Hu et al , ), which showed > 2‐fold increased RNA interaction, and Rpb7, which was identified in PAR‐TRAPP exclusively under stress conditions. Rpb7 is a component of RNAPII, but dissociates following stress and participates in mRNA decay (Lotan et al , ; Harel‐Sharvit et al , ), presumably explaining its detection only following sorbic acid treatment.…”

Defining the RNA Interactome by Total RNA-Associated Protein Purification

“…It was, therefore, unexpected that reduced RNA interactions were seen for eleven proteins classed under the GO term "P-body". Exceptions included the global translation repressor Ssd1 (Hu et al, 2018;Kurischko et al, 2011), which showed >2-fold increased RNA interaction, and Rpb7, which was identified in PAR-TRAPP exclusively under stress conditions. Rpb7 is a component of RNAPII, but dissociates following stress and participates in mRNA decay (Harel-Sharvit et al, 2010;Lotan et al, 2007), presumably explaining its detection only following sorbic acid treatment.…”